Since 1961, the Clinical Neurophysiology Program (CNP) at UCLA has made use of the unique opportunities provided by an epilepsy surgery facility to carry out direct research on the human brain. In the sixties and seventies, emphasis was placed on clinical research directed toward improving the diagnosis and surgical treatment of epilepsy, although basic research has always been an important part of the program. Over the past 20 years, resective surgery has become sufficiently accepted as a safe and effective mode of treatment for partial epilepsy to allow clinical activities of the CNP to be supported by hospital funds or supplemented by grants awarded to develop specific diagnostic techniques. We have requested support only for basic research projects that take advantage of knowledge gained from animal studies and the clinical setting to investigate fundamental mechanisms of normal and abnormal brain function. We are further focusing our research efforts only on basic mechanisms of human temporal lobe epilepsy associated with hippocampal sclerosis. Information from patients in our epilepsy surgery facility will be utilized by a multi disciplinary team of basic and clinical neuroscientists to define molecular biological, anatomical, and physiological substrates of epileptiform cerebral processes. In this renewal application, we propose to: 1.) examine alterations in molecular signals, cellular morphologies, synaptic organizations, and neurotransmitter localization in epileptogenic tissue; 2.) relate these findings to results of in vitro and in vivo electrophysiological and in vivo microdialysis studies of neuronal activity in the same brain regions; 3.) examine the possible role of glial influences in these abnormal neuronal properties; and 4.) use these data to characterize the fundamental mechanisms of epileptogenesis in the human hippocampus. The long-term objectives of the CNP are to: 1.) reveal cellular and synaptic mechanisms of epileptogenesis in order to suggest new medical, as well as surgical, approaches to antiepileptic therapy; and 2.) better understand the basis of pathological disruption of normal neuronal activity that results in abnormal behavior, in order to prevent or more effectively treat interictal behavioral disturbances associated with epilepsy and other neurological disorders.